It is generally accepted that tumours arise through the accumulation of several changes affecting the control of cell growth. Recent advances in molecular biology have made it possible to define some of these changes in molecular terms and to trace the steps by which certain tumours evolve.

Evolution of tumours and the impact of molecular oncology.

https://www.cell.com/cell/pdf/0092-8674(89)90238-9.pdf

Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene

Genes that can inhibit the expression of the tumorigenic phenotype have been detected by the fusion of normal and malignant cells, the phenotypic reversion of in vitro transformants, the induction of terminal differentiation of malignant cell lineages, the loss of "recessive cancer genes," the discovery of regulatory sequences in the immediate vicinity of certain oncogenes, and the inhibition of tumor growth by normal cell products Such tumor suppressor genes will probably turn out to be as, if not more, diversified as the oncogenes Consideration of both kinds of genes may reveal common or interrelated functional properties

The Approaching Era of the Tumor Suppressor Genes

Both tumorigenic segregant HeLa X human fibroblast hybrids and tumorigenic HeLa (D98/AH-2) cells can be converted to a non-tumorigenic state following introduction of a single copy of a fibroblast t(X;11) chromosome. The translocated chromosome contains approximately 95% of the 11 chromosome and the q26-qter portion of the X chromosome which contains the hypoxanthine guanine phosphoribosyl transferase (HPRT) gene. Introduction of a human X chromosome has no effect on tumorigenic expression. Suppression of tumorigenicity is relieved by selecting cells which have lost the t(X;11) chromosome by growth in medium containing 6-thioguanine (6-TG). Further, reintroduction of the t(X;11) chromosome into tumorigenic 6TGR cells again suppresses tumorigenicity. Thus, the introduction of a single copy of a human chromosome 11 is sufficient to completely suppress the tumorigenic phenotype of HeLa cells and is suggestive of the presence of tumor-suppressor gene(s) on this chromosome.

Introduction of human chromosome 11 via microcell transfer controls tumorigenic expression of HeLa cells.

Structural rearrangements involving the short arm of chromosome 9, including bands 9p21 and 22, are found in the leukemia cells of 7 to 13 percent of patients with acute lymphoblastic leukemia. The interferon-α gene cluster and the interferon-β1 gene have been localized to this chromosomal region. We have previously demonstrated deletions of these genes in several cell lines established in vitro from patients with lymphoblastic leukemia. We report here homozygous or hemizygous deletions of the interferon-α and interferon-β1 genes in samples of leukemia cells from patients with lymphoblastic leukemia. Of 62 patients examined, 18 (29 percent) had such deletions. Four patients (7 percent) had homozygous deletions of the interferon-α gene cluster; of these, one also had a homozygous deletion and three had hemizygous deletions of the interferon-β1 gene. Fourteen patients (23 percent) had hemizygous deletions of both the interferon-α gene cluster and the interferon-β1 gene. In 8 of the 18 patients with...

https://www.nejm.org/doi/pdf/10.1056/NEJM199001113220202

Deletions of interferon genes in acute lymphoblastic leukemia.

Previous experiments with crosses between malignant and diploid mouse cells had shown that the reappearance of malignancy in hybrids in which it was initially suppressed was associated in some cases with the elimination of the chromosomes 4 derived from the diploid parent cell. In others, however, this did not appear to be so. In the present study, we have re-examined the role of the diploid chromosomes 4 in the suppression of malignancy using natural polymorphisms of the centromeric heterochromatin to identify the parental origin of the chromosomes 4 in the hybrid cells. We now find that the diploid chromosomes 4 are indeed involved in the suppression of malignancy in all the tumours that we have examined, which include a carcinoma, a melanoma, a sarcoma and a lymphoma. In all crosses between these malignant tumour cells and diploid fibroblasts, there is selective pressure in vivo against the chromosomes 4 derived from the diploid cell and in favour of the chromosomes 4 derived from the malignant cell. This indicates that the chromosomes 4 in all these tumours are in some way functionally different from the chromosomes 4 of the diploid fibroblast. Reappearance of malignancy in hybrids in which it was initially suppressed may result from a reduction in the number of diploid chromosomes 4, an increase in the number of malignant chromosomes 4, or both. The gene on the diploid chromosome 4 responsible for the suppression of malignancy acts in a dose-dependent manner.

R. Hennion

Papers

The analysis of malignancy by cell fusion ix.* re-examination and clarification of the cytogenetic problem